Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.

Detaljer

Författare
  • Rishi V Puram
  • Monika S Kowalczyk
  • Carl G de Boer
  • Rebekka K Schneider
  • Peter G Miller
  • Marie McConkey
  • Zuzana Tothova
  • Héctor Tejero
  • Dirk Heckl
  • Marcus Järås
  • Michelle C Chen
  • Hubo Li
  • Alfred Tamayo
  • Glenn S Cowley
  • Orit Rozenblatt-Rosen
  • Fatima Al-Shahrour
  • Aviv Regev
  • Benjamin L Ebert
Enheter & grupper
Externa organisationer
  • Harvard University
  • Broad Institute
  • Spanish National Cancer Research Center (CNIO)
  • Brigham and Women's Hospital / Harvard Medical School
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cell- och molekylärbiologi
Originalspråkengelska
Sidor (från-till)303-16
Antal sidor14
TidskriftCell
Volym165
Utgivningsnummer2
StatusPublished - 2016
PublikationskategoriForskning
Peer review utfördJa